Cancer refers to more than one hundred clinically distinct forms of the disease. Almost every tissue of the body can give rise to cancer and some can even yield several types of cancer. Cancer is characterized by an abnormal growth of cells which can invade the tissue of origin or spread to other sites. In fact, the seriousness of a particular cancer, or the degree of malignancy, is based upon the propensity of cancer cells for invasion and the ability to spread. That is, various human cancers (e.g., carcinomas) differ appreciably as to their ability to spread from a primary site or tumor and metastasize throughout the body. Indeed, it is the process of tumor metastasis which is detrimental to the survival of the cancer patient. A surgeon can remove a primary tumor, but a cancer that has metastasized often reaches too many places to permit a surgical cure. To successfully metastasize, cancer cells must detach from their original location, invade a blood or lymphatic vessel, travel in the circulation to a new site, and establish a tumor.
The twelve major cancers are prostate, breast, lung, colorectal, bladder, non-Hodgkin's lymphoma, uterine, melanoma, kidney, leukemia, ovarian, and pancreatic cancers. Often, cancers may be more or less effectively treated with chemotherapeutic agents (also referred to as cytotoxic drugs). However, chemotherapeutic agents suffer from two major limitations. First, chemotherapeutic agents are not specific for cancer cells and particularly at high doses, they are toxic to normal rapidly dividing cells. Second, with time and repeated use cancer cells develop resistance to chemotherapeutic agents thereby providing no further benefit to the patient. Subsequently, other treatment modalities have been investigated to address the limitations imposed by the use of chemotherapeutic agents. Alternative, well-studied treatment options are surgery, radiation and immunotherapy. However, these treatments also have serious limitations especially in more advanced cancers. Thus, for example, surgery is limited by the ability to completely remove extensive metastases, radiation is limited by the ability to selectively deliver radiation and penetrate cancer cells and immunotherapy (e.g., use of approved cytokines) is limited by the balance between efficacy and toxicity. For this reason, other relatively newer therapeutic approaches are under study. These approaches include the use of protein kinase inhibitors (not selective and therefore toxic and still prone to drug resistance), antiangiogenesis agents (limited efficacy and toxicity) and gene therapy (no significant success to date). Therefore, a need still exists for novel compounds which are efficacious (e.g., reduce tumor size and/or spread of metastases) and have reduced toxicity for the treatment of cancer.
The present invention addresses the need for compounds, pharmaceutical compositions and treatment methods for the treatment of cancers. Additional features of the invention will be apparent from a review of the disclosure, figures and description of the invention herein.